1. Field of the Invention
This invention pertains to novel oral antiseptic compositions useful in promoting oral hygiene. The novel compositions are prepared by combining a therapeutically effective amount of a synergistic antiseptic composition comprising a hexahydro-5pyrimidinamine compound and thymol in an oral vehicle or in a pharmaceutically acceptable carrier such as a confectionery bulking agent. Such oral antiseptic compositions are useful against the bacteria most commonly associated with the formation of dental plaque and caries such as Streptococcus sanguis and Streptococcus mutans, respectively. The synergistic antiseptic compositions may be utilized in a wide variety of aqueous-based oral antiseptic products and confectionery products. This invention also relates to methods by which these oral antiseptic and confectionery products may be prepared.
2. Description of the Prior Art
Hexahydro-5-pyrimidinamine compounds (5-aminohexahydropyrimidine), such as hexetidine, which is also known as 1,3-bis(2-ethylhexyl)-hexahydro-5-methyl-5-pyrimidinamine, are well known in the art for their broad spectrum antimicrobial activity. These hexahydro-5-pyrimidinamine compounds are used in aqueous-based oral compositions for the treatment of oral infections such as gingivitis, oral ulcers, periodontal disease, and for the control of mouth odor.
Hexetidine is a saturated pyrimidine derivative which is soluble in most organic solvents and practically insoluble in water. The use of hexetidine at therapeutic levels, as the free base or salt, has many organoleptic disadvantages. These disadvantages include, for example, brown staining of dental enamel and bitter taste. Significant effort has been expended towards overcoming these undesirable side effects.
U.S. Pat. No. 2,837,463, issued to Fondick et al. and assigned to Warner-Lambert Company, discloses therapeutic compositions which comprise certain hexahydro-5-pyrimidinamine compounds and a pharmaceutical carrier. The hexahydro-5-pyrimidinamine compound may be hexetidine and the therapeutic compositions may contain optional additives such as menthol to add flavor.
U.S. Pat. No.4,141,968, issued to Kunz et al. and assigned to Doll GmbH, West Germany, discloses the preparation and use of certain substituted benzoic acid salts of hexetidine, particularly the terephthalic acid and 4-sulfamylbenzoic acid salts. These salts are said to have useful bacteriostatic activity. The benzoic acid salt component may be monosubstituted or disubstituted. The substituent groups on benzoic acid are selected from the group consisting of -COOH, -OH, -NH.sub.2, -SO.sub.3 H and -SO.sub.2 NH. When the substituent group is -COOH or -OH, the group must be located in the 4-position (para) on the benzoic acid moiety. When the benzoic acid salt component is disubstituted, the substituent groups must be different from each other. Substituent groups located at the 4-position on the benzoic acid ring are particularly preferred. Examples of the preferred substituted benzoic acid salts of hexetidine include:
1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5-pyrimidinamine terephthalate PA0 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5-pyrimidinamine 4-sulfamylbenzoate PA0 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5-pyrimidinamine 4-hydroxybenzoate PA0 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5-pyrimidinamine 2-aminobenzoate PA0 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5-pyrrimidinaine 4-aminobenzoate PA0 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5-pyrimidinamine 4-aminosalicylate PA0 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5-pyrimidinaine 5-sulfosalicylate
U.S. Pat. No. 4,206,198, issued to Schmolka and assigned to BASF Wyandotte Corporation, discloses a dentifrice composition which contains a foam producing amount of a nonionic surfactant and a cationic antidecay agent. The nonionic surfactant is an ethoxylated adduct of a C-15 or C-16 fatty alcohol. The cationic antidecay agent may be hexetidine and the dentifrice composition may contain optional flavoring additives such as eucalyptus and sodium methylsalicylate.
U.S. Pat. No. 4,323,552, issued to Schmolka and assigned to BASF Wyandotte Corporation, discloses a high foaming dentifrice gel composition said to be compatible with antimicrobial agents. The gel composition comprises a nonionic surfactant and a cationic antidecay agent. The nonionic surfactant is a cogeneric mixture of conjugated polyoxybutylenepolyoxyethylene polymeric compounds with the polyoxybutylene polymers in the mixture having an average molecular weight of at least 500. The cationic antidecay agent may be hexetidine and optional flavoring additives such as eucalyptus and sodium methylsalicylate may be included in the high foaming dentifrice gel composition.
U.S. Pat. No. 4,343,785, issued to Schmolka and assigned to BASF Wyandotte Corporation, discloses a gel dentifrice composition said to retains its gel properties at low temperatures. The gel dentifrice contains about 15% of a cogeneric mixture of conjugated polyoxybutylene-polyoxyethylene block copolymers, an effective amount of an essential additive and less than about 85% water. The average molecular weight of the polyoxybutylene polymers in the mixture is at least 1200. Additional requirements relate the hydrophobic molecular weight of the polyoxybutylenepolyoxyethylene block copolymers to the minimum polyethylene content and the minimum block copolymer content. The essential additive in the gel dentifrice composition may be hexetidine and optional flavoring agents such as eucalyptus and sodium methylsalicylate may be included in the gel.
U.S. Pat. No. 4,522,806, issued to Muhlemann et al. and assigned to Lever Brothers Company, discloses an antiplaque composition which contains the combination of hexetidine, as the water-insoluble pyrimidine base, plus one or more zinc cationic salts. The antiplaque composition is said not to stain teeth.
U.S. Pat. No. 4,574,081, issued to Shymon and assigned to Colgate-Palmolive Company, discloses an antiplaque dentifrice having an improved flavor comprising an antiplaque compound, which may be hexetidine, a flavoring agent which consists essentially of at least 15% anethol, up to 46% menthol, up to 39% peppermint, and a sweetening agent in a dental vehicle containing a dental abrasive.
U.S. Pat. No. 4,624,849, issued to Toogood and assigned to The Proctor & Gamble Company, discloses a noncariogenic therapeutic lozenge comprising a cationic antimicrobial agent and a nonionic lubricant in a pharmaceutically acceptable carrier. The antimicrobial agent may be hexetidine and the lubricant is selected from the group consisting of polyethylene glycols, hydrogenated tallow and hydrogenated vegetable oil.
U.S. Pat. No. 4,666,517, issued to Bakar and assigned to Colgate-Palmolive Company, discloses an oral antiplaque and antigingivitis composition comprising a synergistic antiseptic combination of hexetidine and tridecanol-1, in the weight ratio of 1:1 to 5:1, respectively.
British patent no. 1,468,557, assigned to Societe Norgan, discloses a pharmaceutical composition said to prolong the antibacterial effect of hexetidine. The composition contains hexetidine, choline salicylate and chlorobutanol in a pharmaceutically acceptable solvent.
While the above hexetidine containing oral antiseptic compositions provide some degree of improved oral antiseptic activity, none of the above compositions can maintain a high level of efficacy without the disadvantages characteristic of hexahydro-5- o pyrimidinamine compounds. Thus it would be commercially advantageous to be able to enhance or potentiate the antiseptic activity of hexahydro-5-pyrimidinamine compounds, such as hexetidine. By increasing the antiseptic activity of the hexahydro-5-pyrimidinamine compound, an antiseptic product could contain less of the antiseptic compound and thus have reduced side effects without a concomitant decrease in therapeutic benefits. The present invention provides such improved oral antiseptic compositions without the disadvantages characteristic of previously known products. The present invention also provides methods by which these improved oral antiseptic compositions may be prepared.